Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 174, No 12

Background: B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness. Objective: To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE. Design: Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003) Setting: England. Participants: Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019. Intervention: Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks. Measurements: The prespecified primary end point was serum IgG anti–double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events. Results: At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data. Limitations: Small sample size; biomarker primary end point. Conclusion: Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy. Primary Funding Source: Versus Arthritis.

Clinical Trends Among U.S. Adults Hospitalized With COVID-19, March to December 2020: A Cross-Sectional Study: Annals of Internal Medicine: Vol 174, No 10

Background: The COVID-19 pandemic has caused substantial morbidity and mortality. Objective: To describe monthly clinical trends among adults hospitalized with COVID-19. Design: Pooled cross-sectional study. Setting: 99 counties in 14 states participating in the Coronavirus Disease 2019–Associated Hospitalization Surveillance Network (COVID-NET). Patients: U.S. adults (aged ≥18 years) hospitalized with laboratory-confirmed COVID-19 during 1 March to 31 December 2020. Measurements: Monthly hospitalizations, intensive care unit (ICU) admissions, and in-hospital death rates per 100 000 persons in the population; monthly trends in weighted percentages of interventions, including ICU admission, mechanical ventilation, and vasopressor use, among an age- and site-stratified random sample of hospitalized case patients. Results: Among 116 743 hospitalized adults with COVID-19, the median age was 62 years, 50.7% were male, and 40.8% were non-Hispanic White. Monthly rates of hospitalization (105.3 per 100 000 persons), ICU admission (20.2 per 100 000 persons), and death (11.7 per 100 000 persons) peaked during December 2020. Rates of all 3 outcomes were highest among adults aged 65 years or older, males, and Hispanic or non-Hispanic Black persons. Among 18 508 sampled hospitalized adults, use of remdesivir and systemic corticosteroids increased from 1.7% and 18.9%, respectively, in March to 53.8% and 74.2%, respectively, in December. Frequency of ICU admission, mechanical ventilation, and vasopressor use decreased from March (37.8%, 27.8%, and 22.7%, respectively) to December (20.5%, 12.3%, and 12.8%, respectively); use of noninvasive respiratory support increased from March to December. Limitation: COVID-NET covers approximately 10% of the U.S. population; findings may not be generalizable to the entire country. Conclusion: Rates of COVID-19–associated hospitalization, ICU admission, and death were highest in December 2020, corresponding with the third peak of the U.S. pandemic. The frequency of intensive interventions for management of hospitalized patients decreased over time. These data provide a longitudinal assessment of clinical trends among adults hospitalized with COVID-19 before widespread implementation of COVID-19 vaccines. Primary Funding Source: Centers for Disease Control and Prevention.

Supplemental Nutrition Assistance Program Participation and Health Care Use in Older Adults: A Cohort Study: Annals of Internal Medicine: Vol 174, No 12

Background: Older adults dually eligible for Medicare and Medicaid have particularly high food insecurity prevalence and health care use. Objective: To determine whether participation in the Supplemental Nutrition Assistance Program (SNAP), which reduces food insecurity, is associated with lower health care use and cost for older adults dually eligible for Medicare and Medicaid. Design: An incident user retrospective cohort study design was used. The association between participation in SNAP and health care use and cost using outcome regression was assessed and supplemented by entropy balancing, matching, and instrumental variable analyses. Setting: North Carolina, September 2016 through July 2020. Participants: Older adults (aged ≥65 years) dually enrolled in Medicare and Medicaid but not initially enrolled in SNAP. Measurements: Inpatient admissions (primary outcome), emergency department visits, long-term care admissions, and Medicaid expenditures. Results: Of 115 868 persons included, 5093 (4.4%) enrolled in SNAP. Mean follow-up was approximately 22 months. In outcome regression analyses, SNAP enrollment was associated with fewer inpatient hospitalizations (−24.6 [95% CI, −40.6 to −8.7]), emergency department visits (−192.7 [CI, −231.1 to −154.4]), and long-term care admissions (−65.2 [CI, −77.5 to −52.9]) per 1000 person-years as well as fewer dollars in Medicaid payments per person per year (−$2360 [CI, −$2649 to −$2071]). Results were similar in entropy balancing, matching, and instrumental variable analyses. Limitation: Single state, no Medicare claims data available, and possible residual confounding. Conclusion: Participation in SNAP was associated with fewer inpatient admissions and lower health care costs for older adults dually eligible for Medicare and Medicaid. Primary Funding Source: National Institutes of Health.

SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting

Background: With the emergency use authorization of multiple vaccines against SARS-CoV-2 infection, data are urgently needed to determine their effectiveness in a real-world setting. Objective: To evaluate the short-term effectiveness of vaccines in preventing SARS-CoV-2 infection. Design: Test-negative case–control study using conditional logistic regression. Setting: U.S. Department of Veterans Affairs health care system. Participants: All veterans who had testing for SARS-CoV-2 infection between 15 December 2020 and 4 March 2021 and no confirmed infection before 15 December 2020. Intervention: SARS-CoV-2 vaccination with either the BNT-162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine as part of routine clinical care. Measurements: Effectiveness of vaccination against confirmed SARS-CoV-2 infection. Results: Among 54 360 persons who tested positive and 54 360 propensity score–matched control participants, the median age was 61 years, 83.6% were male, and 62% were White. Median body mass index was 31 kg/m2 among those who tested positive and 30 kg/m2 among those who tested negative. Among those who tested positive, 9800 (18.0%) had been vaccinated; among those who tested negative, 17 825 (32.8%) had been vaccinated. Overall vaccine effectiveness 7 or more days after the second dose was 97.1% (95% CI, 96.6% to 97.5%). Effectiveness was 96.2% (CI, 95.5% to 96.9%) for the Pfizer–BioNTech BNT-162b2 vaccine and 98.2% (CI, 97.5% to 98.6%) for the Moderna mRNA-1273 vaccine. Effectiveness remained above 95% regardless of age group, sex, race, or presence of comorbidities. Limitations: Predominantly male population; lack of data on disease severity, mortality, and effectiveness by SARS-CoV-2 variants of concern; and short-term follow-up. Conclusion: Currently used vaccines against SARS-CoV-2 infection are highly effective in preventing confirmed infection in a high-risk population in a real-world setting. Primary Funding Source: None.

Influenza Vaccine Uptake and Missed Opportunities Among the Medicare-Covered Population With High-Risk Conditions During the 2018 to 2019 Influenza Season: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 175, No 1

Background: Seasonal influenza causes substantial morbidity and mortality among older U.S. adults and those with comorbid health conditions. Objective: To describe seasonal influenza vaccine uptake and identify factors associated with missed opportunities for influenza vaccination. Design: Retrospective cohort study. Setting: Medicare fee-for-service claims. Participants: 31.6 million U.S. adults continuously enrolled under Medicare Parts A and B during the 2018 to 2019 influenza season. Measurements: Influenza vaccine uptake and missed opportunities by patient demographic characteristics, high-risk status (that is, ≥1 condition increasing influenza complication risk), Medicare–Medicaid dual-eligibility status, and health care provider visits (that is, vaccination opportunities). Results: Overall, 50.5% of beneficiaries aged 19 years or older had Medicare claims for influenza vaccination: 31.6% among people aged 19 to 64 years and 54% among people aged 65 years or older. More White beneficiaries were vaccinated (52.9%) than Black (34.9%) or Hispanic (30.4%) beneficiaries. Uptake was higher (56.1%) for beneficiaries with high-risk conditions than for those without (27.6%). Among unvaccinated beneficiaries overall, 77.4% visited a provider during influenza season; among unvaccinated beneficiaries with and without high-risk conditions, 91% and 43%, respectively, had seen a provider at least once. The proportion of beneficiaries with missed opportunities for influenza vaccination was 44.2% and was higher for beneficiaries in the non–high-risk group (59.1%) than those in the high-risk group (42.2%). Uptake was lower and proportions of missed opportunities were higher among beneficiaries in younger age groups, of Black and Hispanic race/ethnicity, without high-risk conditions, or with Medicare-Medicaid dual eligibility. Limitations: Influenza vaccinations without claims could not be captured. Data on reasons for nonvaccination were unavailable. Conclusion: Influenza vaccination coverage for Medicare beneficiaries continues to be suboptimal, with missed opportunities despite availability of influenza vaccination with no copayment. Disparities persist in vaccination uptake by race/ethnicity. Primary Funding Source: None.

Trends in Outpatient Care for Medicare Beneficiaries and Implications for Primary Care, 2000 to 2019

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: Despite the central role of primary care in improving health system performance, there are little recent data on how use of primary care and specialists has evolved over time and its implications for the range of care coordination needed in primary care. Objective: To describe trends in outpatient care delivery and the implications for primary care provider (PCP) care coordination. Design: Descriptive, repeated, cross-sectional study using Medicare claims from 2000 to 2019, with direct standardization used to control for changes in beneficiary characteristics over time. Setting: Traditional fee-for-service Medicare. Patients: 20% sample of Medicare beneficiaries. Measurements: Annual counts of outpatient visits and procedures, the number of distinct physicians seen, and the number of other physicians seen by a PCP's assigned Medicare patients. Results: The proportion of Medicare beneficiaries with any PCP visit (66.1% in 2000 to 75.8% in 2019) or specialist visit (68.9% to 76.1%) annually increased. The mean annual number of primary care office visits per beneficiary changed little from 2009 to 2019 (3.25 to 3.48; 7.1% increase), although the mean number of PCPs seen increased from 0.96 to 1.41 (46.9% increase). In contrast, the mean annual number of visits to specialists increased 28.3% from 4.42 to 5.67, whereas the mean number of unique specialists seen increased 43.5% from 1.77 to 2.54. The proportion of beneficiaries seeing 5 or more physicians annually increased from 19.1% to 35.1%. In 2000, a PCP’s Medicare patient panel saw a median of 52 other physicians (interquartile range, 23 to 87), increasing to 95 (interquartile range, 40 to 164) in 2019. Limitation: Data were limited to Medicare beneficiaries and, because of the use of a 20% sample, may underestimate the number of other physicians seen across a PCP's entire panel. Conclusion: Outpatient care for Medicare beneficiaries has shifted toward more specialist care received from more physicians with modestly increased primary care contact. This represents a substantial expansion of the coordination burden faced by PCPs. Primary Funding Source: National Institute on Aging.

A Cross-Sectional Study of SARS-CoV-2 Vaccination Among Employees of an Urban Safety-Net Health Care System

What Will It Take to End HIV in the United States?: A Comprehensive, Local-Level Modeling Study: Annals of Internal Medicine: Vol 174, No 11

Background: The Ending the HIV Epidemic (EHE) initiative aims to reduce incident HIV infections by 90% over a span of 10 years. The intensity of interventions needed to achieve this for local epidemics is unclear. Objective: To estimate the effect of HIV interventions at the city level. Design: A compartmental model of city-level HIV transmission stratified by age, race, sex, and HIV risk factor was developed and calibrated. Setting: 32 priority metropolitan statistical areas (MSAs). Patients: Simulated populations in each MSA. Intervention: Combinations of HIV testing and preexposure prophylaxis (PrEP) coverage among those at risk for HIV, plus viral suppression in persons with diagnosed HIV infection. Measurements: The primary outcome was the projected reduction in incident cases from 2020 to 2030. Results: Absent intervention, HIV incidence was projected to decrease by 19% across all 32 MSAs. Modest increases in testing (1.25-fold per year), PrEP coverage (5 percentage points), and viral suppression (10 percentage points) across the population could achieve reductions of 34% to 67% by 2030. Twenty-five percent PrEP coverage, testing twice a year on average, and 90% viral suppression among young Black and Hispanic men who have sex with men (MSM) achieved similar reductions (13% to 68%). Including all MSM and persons who inject drugs could reduce incidence by 48% to 90%. Thirteen of 32 MSAs could achieve greater than 90% reductions in HIV incidence with large-scale interventions that include heterosexuals. A web application with location-specific results is publicly available (www.jheem.org). Limitation: The COVID-19 pandemic was not represented. Conclusion: Large reductions in HIV incidence are achievable with substantial investment, but the EHE goals will be difficult to achieve in most locations. An interactive model that can help policymakers maximize the effect in their local environments is presented. Primary Funding Source: National Institutes of Health.

Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants: A Nationwide Propensity Score–Weighted Study: Annals of Internal Medicine: Vol 174, No 11

Background: Gastrointestinal bleeding (GIB) rates for direct oral anticoagulants (DOACs) and warfarin have been extensively compared. However, population-based studies comparing GIB rates among different DOACs are limited. Objective: To compare rates of GIB among apixaban, dabigatran, and rivaroxaban. Design: Nationwide population-based cohort study. Setting: Landspítali–The National University Hospital of Iceland and the 4 regional hospitals in Iceland. Patients: New users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Measurements: Rates of GIB were compared using inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression. Results: In total, 2157 patients receiving apixaban, 494 patients receiving dabigatran, and 3217 patients receiving rivaroxaban were compared. For all patients, rivaroxaban had higher overall rates of GIB (3.2 vs. 2.5 events per 100 person-years; hazard ratio [HR], 1.42 [95% CI, 1.04 to 1.93]) and major GIB (1.9 vs. 1.4 events per 100 person-years; HR, 1.50 [CI, 1.00 to 2.24]) compared with apixaban. Rivaroxaban also had higher GIB rates than dabigatran, with similar point estimates, although the CIs were wider and included the possibility of a null effect. When only patients with atrial fibrillation were included, rivaroxaban was associated with higher rates of overall GIB than apixaban (HR, 1.40 [CI, 1.01 to 1.94]) or dabigatran (HR, 2.04 [CI, 1.17 to 3.55]). Dabigatran was associated with lower rates of upper GIB than rivaroxaban in both analyses. Limitations: Unmeasured confounding and small subgroup analyses. Conclusion: Rivaroxaban was associated with higher GIB rates than apixaban and dabigatran regardless of treatment indication. Primary Funding Source: Icelandic Centre for Research and Landspítali–The National University Hospital of Iceland.

Sickle Cell Disorders and Severe COVID-19 Outcomes: A Cohort Study